Metabolic signature of the pathogenic 22q11.2 deletion identifies carriers and provides insight into systemic dysregulation

Background Large deletions at chromosome 22q11.2 are known to cause severe clinical conditions collectively known as 22q11.2 deletion syndrome. Notwithstanding the pathogenicity of these deletions, affected individuals are typically diagnosed in late childhood or early adolescence, and little is known of the molecular signaling cascades and biological consequences immediately downstream of the deleted genes. Methods Here, we used targeted metabolomics to compare neonatal dried blood spot samples from individuals clinically identified as carriers of a 3MB deletion at the chromosome 22q11.2 with unaffected individuals. A total of 173 metabolites were successfully identified and used to inform on systemic dysregulation caused by the genomic lesion and to discriminate carriers from non-carriers. Results We found 84 metabolites to be differentially abundant between carriers and non-carriers of the 22q11.2 deletion. A predictive model based on all 173 metabolites achieved high Accuracy (89%), Area Under the Curve (93%), F1 (88%), Positive Predictive Value (94%) and Negative Predictive Value (84%) with tyrosine and proline having the highest individual contributions to the model as well as the highest interaction strength. Conclusions Targeted metabolomics provides insight into the molecular consequences possibly contributing to the pathology underlying the clinical manifestations of the 22q11 deletion and is an easily applicable approach to first-pass screening for carrier status of the 22q11 to prompt subsequent verification of the genomic diagnosis. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The iPSYCH Initiative is funded by the Lundbeck Foundation (Grant Nos. R268-2016-3925, R102-A9118, and R155-2014- 1724). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The scientific board of the Danish Cytogenetic Central Register approved the study and provided access to the genetic data, that provided information on individuals with a 22q11.2 deletion and was obtained from the Danish Cytogenetic Central Registry (DCCR), which was established in 1968 and contains data on every karyotype obtained by clinical departments performing chromosomal analyses in Denmark. The project was approved by the scientific ethic committees (Videnskabsetiske Komiteer, Reg.nr: H-B-2009-026) and the Danish Data Protection Agency (Datatilsynet, Reg.nr: 2007-58-0015). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data underlying this study are not publicly available due to the Danish Data Protection Act and European Regulation 2016/679 of the European Parliament and of the Council (GDPR) that prohibit distribution of personal data. The data are available from the corresponding authors upon reasonable request and under a data transfer and collaboration agreement.